6-fluoro steroids



1 2,838,503 6-FLUOR0 STEROIDS Milton E. Herr, Kalamazoo, John C. Babcock, Portage Township, Kalamazoo County, and J Allan Campbell, John A. i-Iogg, and Raymond L. Pederson, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Micln, a corporation of Michigan No Drawing. Application February 19, 1958 Serial No. 716,038 40 Claims. (Cl. 260-23955) difluoro-l l-keto-17ot alkyltestosterones), 6,9ot difluoro-T 175-1ydroxy-17ot-alkyl-19-nor-4-androstene 3,11 diones 6,9ot-difluoroll-keto-17a-alkyl-19-nortestosterones) 6,9ot-

atent l difiuoro-l1p,l7,8-dihydroxy-17ot-alkyl-4-androsten 3-ones terones), the 17-acylates thereof and novel steroid interwherein R represents hydrogen or methyl, R represents a lower alkyl radical, R represents hydrogen or an acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, Y represents hydrogen or fluorine, and X represents a carbonyl radical v( C'=-O) or a hydroxymethylene radical CHOH). The term lower alkyl radical as used herein refers to an alkyl radical of from one to eight carbon atoms, inclusive, e. g., methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, 3- methylpentyl, octyl, and the like.

It is an object of the present invention to provide novel 6-fiuoro-17fl-hydroxy-17ot-alkyl-4-androstene-3,11- diones, 6-fluoro-17B-hydroxy-l7a-alkyl-l9-nor-4-androstene-3,l1-diones, 6-fluoro-115,17B-dihydroxy-17a-alkyl- 4-androsten-3-ones, 6-fluoro-115,l7fl-dihydroxy-l7a-alkyl- 19-nor-4-androsten-3-ones, 6,9ot-difluoro 175 hydroxy- 17a-alkyl-4-androstene-3,1l-diones, 6,9u-ditluoro-17B-hydroxy-l'lu-alkyl-19-nor-4-androstene-3,1l-diones, 6,9oc-difluoro-l1o,l7B-dihydroxy-17ct-alltyl-4-androsten' 3-ones, 6,9a-difiuoro11/3,17B-dihydroxy-17a-alkyl-l9-nor 4 androsten-3-ones, the l7-acylates thereof, and novel intermediates and methods in the A production thereof. Other objects will be apparent to those skilled in the art towhich this invention pertains,

Patented June it The novel end products of this invention, the compounds of Formula I, possess useful therapeutic properties. They are orally, active anabolic-androgenic agents. The compounds of Formula I affect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens, e. g., ethinylestradiol, reduce fertility and constitute effective therapy for dysrnenorrhea, amenorrhea, endometriosis, threatened absortion and related gynecological disorders. Administration of the steroids of Formula I can be in conventional dosage forms such as pills, tablets, capsules, syrups, or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injectable products.

The compounds of Formula I, are prepared according to the following reaction sequence:

wherein R, R X and Y have the same meaning previ-- and Ac represents the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive.

Compounds of the type represented by Formula II, for example, 17,8-hydroxy-17a-alkyl-4-androstene-3,l l-diones and 17,8-hydroxy-17a-alkyl-19-nor-4-androstene-3,1 l-diones, are allowed to'react with a diol, preferably ethylene glycol, in the presence of a strong acid such as toluenesulfonic acid, orthochlorobenzenesulfonic acid, sulfuric acid, and the like, to produce. the compounds of Formula III, for example, 17B-hydroxy-17a-alkyl-5-androstene-3,- ll-dione 3-ethylene ketals and 17,8-hydroxy-l7u-alkyl-19- nor-5-androstene-3,1l-dione 3-ethylene ketals. Similarly the compounds of Formula II can be allowed to react with other 1,2-alkane diols or 1,3-alkane diols such as propylene glycol, butane-1,2-diol, butane-1,3-diol, pentane- 1,2- and 1,3-diol, hexane-1,2- and 1,3-diol, heptane-1,2- and 1,3-diol, octane-1,2- "and 1,3-diol or other alkane diols of the formula:

wherein n is an integer having a value of from one to two, inclusive, and R and R each represent hydrogen or lower alkyl radicals containing up to six carbon atoms and wherein the total number of carbon atoms in the alkane diol is up to and including eight carbon atoms, to obtain the corresponding 3-alkylene ketals of Formula III.

The thus-obtained compounds of Formula III are treated with a reducing agent, preferably lithium aluminum hydride, in the presence of an inert organic solvent, for example, anhydrous ether, and preferably under nitrogen, to convert them into the compounds of Formula VI, for example, 1 1/3,17/3-dihydroxy-17u-alkyl-S-androsten-B-one 3-ethylene ketals and 11/3,17,8-dihydroxy-17a-alkyl-19- nor-5-androsten-3-one 3-ethylene ketals.

The compounds of Formulae III and VI are then allowed to react with a peracid such as peracetic or perbenzoic acid to obtain the corresponding 5,6-epoxy-11- oxygenated compounds represented by Formula IV, for example, 5a,6aepoxy-17 3-hydroxy-17a-alkylandrostane-3,- ll-dione 3-ethylene ketals and 5u,6a-epoxy-17fi-hydroxy- 17a-alkyl-19-norandrostane-3,ll-dione 3-ethylene ketals, produced from'the compounds of Formula III, and 5a,6aepoxy-11/8,17/3-dihydroxy-17a-alkylandrostan 3 one 3- ethylene ketals and 5u,6a-epoxy-11fi,l7fl-dihydroxy-17ocalkyl-l9-norandrostan-3-one 3-ethylene ketals, produced from the compounds of Formula VI.

The thus-obtained compounds of Formula IV, for example, 5oc,6a-epoxy-1l-oxygenated compounds, are then treated with a fluorine releasing agent, for example, hydrofluoric acid, in the presence of an organic solvent inert to the reaction, preferably methylene chloride, to obtain the compounds f Formula V, for example, GB-flHOIO-Sa; 17,3-dihydroxy-17a-alkylandrostane-3,1l-diones, 6 3-fluorooz,17,6-dihydroxy-l7m-alkyl-l9-norandrostane-3,1 l-diones, 6fl-fluoro-5a,115,17,8-trihydroxy 17cc alkylandrostan 3- ones and 6e-fluoro-5u,11,8,17,6-trihydroxy-17u-alkyl-19- norandrostan-3-ones and are recovered by conventional means,'such as for example, chromotography.

The thus-obtained compounds of Formula V are then allowed to react with a mineral acid such as hydrochloric acid to convert them into the compounds of Formula I such as, 6a fiuoro-1hit-hydroxy-l7a-alkyl-4-androstene-3,- ll-diones, 6a-fluoro-1'Z/3-hydroxy-17a-alkyl-l9-nor-4-androstene-3,ll-diones, 6a-fiuoro-1 113,175 dihydroxy 17aalkyl-4-androsten-3-ones and 6ot-fluoro-1lp,17fi dihydroxy-17a-alky1-l9-nor 4 androsten 3 ones. The reaction is carried out in a liquid medium such as an organic solvent, for example, chloroform, methylene chloride, ether, and the like, and in the presence of a prototropic agent (a proton donating agent) such as water, alcohols, and organic acids while maintaining the temperature at zero degrees centigrade or slightly lower. Ad-

vantageously, such temperatures should be maintained throughout the period of contact with the acid. Following the termination of the reaction, the reaction mixture can then be Washed with successive portions of water, a 5 solution of alkali, such as sodium bicarbonate, and water, and evaporated to obtain the Ba-fiuoro compounds of Formula I.

The l7-acylates represented for Formula I (ester) are obtained by allowing the compounds of Formula I to re- 10 act with the anhydride of an organic carboxylic acid, particularly a hydrocarbon carboxylic acid, containing from one to twelve carbons, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain l5 aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric,

a cycloaliphatic saturated acid, e. g., cyclohexane-carboxylic, an alkaryl acid, e. g., benzoic, phenylacetic, 2- phenylpropionic, o-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., 0 sodium, salts), e. g., succinic, adipic, a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, cinnamic, a dibasic unsaturated acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., maleic and citraconic. The 17-acylates represented by Formula I (ester) are recovered by conventional means such as crystallization or chromatographic techniques.

I An alternative and the preferred method for the preparation of the compounds of Formulae I and Hester), when Y represents fluorine, for example, 60:,9ot-dlfill0f0- 1lfl,17 8-dihydroxy-17a-alkyl-4-androsten-3-ones, 611,90:-

difluoro-11/3,l7/3-dihydroxy l7a-alkyl-4-androsten-3-one l7-acylates, 6a,9a difluoro 17/9 hydroxy l7a-alkyl-4- androstene-3 ,1 l-dione, 6a,9a-difluoro-17;8-hydroxy-17a alkyl-4-androstene-3,1l-dione l7-acylates and their corre- 5 sponding 19-nor compounds, is represented by the following reaction sequence:

CH3 CH3 ?R2 $112 Y I R R I (Y=H) VII r i ,0 i

C 3 CH3 C 3 CHa (ER; (BB:

----Ri R;

Y R R i/ comprises treating the compounds of Formula I-(Y =H),

according to procedures disclosed in U. S. Patent 2,793,218 as follows: 1

Compounds of the type represented by Formula I (Y=H), for example, 6a-fluoro-11,8,17fl-dihydroxy-l7aalkyl-4-androsten-3-ones and 6-fluoro-11fl,17;8-dihydroxy- 17m-alkyl-19-nor 4-androsten-3 ones are treated according to the procedure disclosed in Example 2 of U. S. Patent 2,793,218 and there are thus-obtained the compounds of Formula VII, for example, 6a-fluoro-9(11)- dehydro-17,6=hydroxy-l7a alkyl-4 androsten-B-ones and 6ot-fluoro-9(l-l)-dehydro-17fi hydroxy-17a-alkyl-19-nor- 4-androsten-3-ones. The compounds of Formula VII are then treated according to the procedure disclosed in Example 5 of U. S. Patent 2,793,218 and there are thusproduced the compounds of Formula VIII, for example, 6u-fiLIOI'O-9rx-hfllO-l 15,17 8 dihydroxy-l7a-alkyl-4-androsten-3-ones and 6a-fluoro-9a-halo-11B,17fi-dihydroxy-l7aalkyl-19-nor-4-androsten-3-ones. The compounds of Formula VIII are then treated according to the procedure disclosed in Example 6 of U. S. Patent 2,793,218 and there are thus-obtained the compounds 'of Formula IX, for example, 6a-fluoro 9,-11 fl-epoxy 17fl-hydroxy-17otalkyl-4 androsten-3-ones and 6u-fluoro-9,1lB-epoxy-UB- hydroxy-17ot-alkyl-19-nor-4-androsten-3-ones. The compounds of Formula IX are then converted into the compounds of Formula I (X= CHOH, Y=F), for example, 6a,9a-difluoro-1'1;3,17B-dihydroxy-17u-alkyl-4-androsten-3-ones and 6a,9a-difiuoro-11,8,17B-dihydroxy-17aalkyl-19-nor-4-androsten-3-ones, by following the'procedure of Example 7 of U. S. Patent 2,793,218. The compounds of Formula I (X= CHOH, Y=F) can then be treated according to the procedure disclosed in Example of U. S. Patent 2,793,218 to obtain the compounds of Formula I (X= C=O, Y=F), for example, 6u,9a-difluoro 17fl-hydroxy-17a-alkyl 4-androstene-3,11-diones and 60,9oc-diflll0lO-17fi hydroxy-17a alkyl-19-nor-4-androstene3,11-diones.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 A. 17B-hydr0xy-17u-methyl-5-androstene-3,1 1-di0ne 3-ethylene ketal (Compound 111a) A stirred mixture containing seven grams of 17fl-hydroxy-17u-methyl-4 androstene-3,11-dione (l1-keto-17- methyltestosterone), Compound Ila, disclosed in U. S. Patent 2,678,933, 350 milliliters of benzene, seven milliliters of ethylene glycol and 42 milligrams of p-toluenesulfonic acid was heated at reflux for a'period of four I a e-"s03 184 degrees centigrade and having an [otl minus 21 degrees (CHCl Analysis.-Calcd. for C22H3204: c, 73.29;H, 8.95.-

Found: C, 73.05; H, 8.80.

B. Set-epoxy 17B-hydr0xy-17u methylandrostene 3,11- dione S-ethylene ketal (Compound 1 Va) liliters of a saturated aqueous sodium bicarbonate solution was added thereto, followed by stirring for five minutes. ous layer and an organic (chloroform solution) layer upon standing for a few minutes. The layers were separated and the chloroform solution layer was washed with water, dried over sodium sulfate and the solvent (chloro form) was removed under reduced pressure to yield a solid residue. The residue was then dissolved in a large volume of ether, concentrated to fifty milliliters, followed by cooling to zero degrees centigrade. lowed by washingwith a little ether and drying, yielded 2.208 grams (seventy percent of theory) of product melting at 203-212 degrees centigrade. Traces of the 5,8,65-

C. 6B-flu0ro 5a,17/3-dihydr0xy-.1 7oc-methylaridrostaneJ;

II-dione (Compound Va) 2.39 grams of Compound IVa dissolved in 22 milliliters of methylene chloride is stirred with 8.3 milliliters of 48 percent hydrofluoric acid in a polyethylene bottle at room temperature for fifty minutes. The mixture thus-obtained is cautiously poured, whilst stirring, into acold solution of twenty grams of sodium bicarbonate in 170 milliliters of water. perature for about thirty minutes, and the insoluble product therein is recovered by filtration, washed with water and methylene chloride and dried. Fluorine and infrared analyses show this crude product to contain 6,6-fluoro-5oz, 1'lfl-dihydroxy-17a-methylandrostane 3,11 dione, Compound Va. volume of methylene chloride and chromatographed over fifty grams of Florisil (synthetic magnesium silicate) and eluted in l00- nilliliter fractions with Skellysolve B hexanes plus increasing proportions of acetone from one to forty percent. Fractions 4-12, containing Compound Va, are combined and evaporated to dryness leaving 6,3- fluoro-5m, l7B-dihydroxy-17a-methylandrostane-3 ,l l-dione as a residue.

D. 6oc-flu0l0-1 7 -hydroxy-1 7a-methyl-4-andr0stene-3J 1- di0ne(6 x-flu0r0 11 keto 17a methyltest sterone) (Compound la) The Compound Va residue obtained in Example 1, Part C, above, is dissolved in milliliters of chloroformand four milliliters of ethanol. The solution is cooled to approximately minus ten degrees centigrade and then treated with anhydrous hydrogen chloride gas for several hours while maintaining the temperature at ap- The reaction mixture was then T he thus-obtained mixture separated into an aque- Filtration fol- The mixture is allowed to stand at room tem- The crude product is'then dissolved in a large B. 6 a-fluoro-I 7 fi-hydroxy-J 7OL-m'8Zhyl-4-l1IZCiI'OStCIl6-3,1 Z

dione 17-pr0pi0nate (6oz fluoro-Il keto Hat-methyltestosterone 17-pr0pi0nate) [Compound Ia (ester)] One gram of Compound Ia in ten milliliters of propionic anhydride is heated at reflux, under nitrogen, until the reaction is substantially complete. The reaction mixture is then cooled, poured into 100 milliliters of water and stirred for several hours, followed by extraction with ether. The ethereal solution is then washed with successive portions of aqueous ten percent sodium hydroxide solution and water, dried over sodium sulfate, followed by removal of the ether by distillation. The residue remaining following distillation is dissolved in methylene chloride and chromatographed over 100 grams of Florisil followed by elution with Skellysolve B hexanes plus increasing proportions of acetone from five to fifty percent. The fractions are examined by infrared analysis and those showing no bands in the hydroxyl region are combined and crystallized to give 6a-fiuoro-17fi-hydroxy-17u-methyl-4-androstene 3,11 dione l7-propionate, Compound Ia(ester).

Similarly, by allowing Compound Ia to react with the appropriate hydrocarbon carboxylic acid anhydride, for example, at temperatures between 100 and 150 degrees centigrade, there are produced other l7-acylates of 6afluoro 175 hydroxy 17a methyl 4 androstene 3,11-dione, such as 6a-fiuoro-l7fi-hydroxy-l7a-methyl-4- androstene-3,ll-dione l7-acetate, 6a-fluoro-l7B-hydroxy- 17a-methyl-4-androstene-3,1l-dione l7-butyrate, 6a-fluoro-l7fi-hydroxy-l7a-methyl-4-androstene-3,l l-dione 17- valerate, 6a-fluoro-17,8-hydroxy-17a-methyl-4-androstene- 3,11-dione l7-hexanoate, 6afiuOI'01713-hYdIOXY-17amethyl-4-androstene-3,1l-dione l7-laurate, 6a-fl1101'O-17flhydroxy-l7a-methyl-4-androstene-3,1 l-dione l7-trimethylacetate, 6 u-fiuorol 7fl hydroxyl 7a-rnethyl-4-androstone-3,11-dione 17-isobutyrate, 6a-fiuoro-l7fi-hydroxy- 17a-methyl-4-androstene-3,1l-dione 17-isovalerate, 6afluoro 17 3 hydroxy 17a methyl 4 androstene 3,11-dione 17-cyclohexane-carboxylate, 6a-fluoro-17fl-hydroxy-l7amethyl-4-androstene-3,l l-dione 17-benzoate, 6a fluoro 17 3 hydroxy 17a methyl 4 androstene-3,ll-dione l7-phenylacetate, 6a-fluoro-l7,B-hydroxy- 17a-methyl-4-androstene-3,l l-dione 17-( fi-phenylpropionate) 6a-fiUOI0- 1 7,8-hydroxyl 7a-methyl-4-androstene-3 ll-dione l7-(o-, m-, p-toluate), 6a-fiuoro-17,8-hydroxy- 17a-methyl-4-androstene-3,1l-dione 17-hemisuccinate, which can be converted with dilute sodium hydroxide to its soluble sodium salt, 6a-fiuoro-l7B-hydroxy-l7a-methyl-4-androstene-3,ll-dione 17-hemiadipate, 6a-fiuoro-l7fihydroxy-17a-methyl-4-androstene-3,1 l-dione 17-acrylate, 6a fluoro 17B hydroxy 17a methyl 4 androstene 3,11-dione l7acrotonate, 6a-fiuoro- 17,6-hydroxy-l 7a-I1'1Cthyl-4-androstene-3,1l-dione 17-undecylenate, 6a-fiuorol7fl-hydroxy-l7a-methyl-4-androstene-3,l l-dione l7-propiolate, 6a-fluoro-l7fl-hydroxy-l7u-methyl-4-androstene- 3,11-dione l7-cinnamate, 6a-fiuoro-l7B-hydroxy-17amethyl-4-androstene-3,ll-dione l7-maleate, and 6a-fluoro-l7fi-hydroxy-17u-methyl-4-androstene-3,1l-dione l7- citraconate. If the corresponding acid anhydride is solid an inert solvent such as toluene, xylene, or dioxane can be added to effect solution and to provide a liquid esterification reaction medium.

EXAMPLE 2 A. 1 7fi-hydroxy-17a-methyl-5-and'r0stene-3,1l-dione 3-ethylene ketal (Compound Illa) A stirred mixture containing 27 grams of Compound Ila, 1400 milliliters of benzene, 27 milliliters of ethylene glycol and 165 milligrams of p-toluenesulfonic acid was heated at reflux for a period of four and one-half hours using a water separator to remove the water of reaction. After refluxing, the mixture was cooled, washed with successive portions of dilute sodium bicarbonate solution and water and then dried over sodium sulfate. The solvent was removed under reduced pressure to give a solid residue of crude Compound HIa.

B. 1 1,8, I 7/3-di/zydroxy-17a-methyl-5-androsten-3-one 3-etlzylene ketal (Compound Vlb) The crude Compound IIIa, obtained in Example 3, Part A, above, was dissolved in 315 milliliters of tetrahydrofuran. The solution thus-obtained was added over a five minute period, under nitrogen, and with stirring, to a mixture of eighteen grams of lithium aluminum hydride in 720 milliliters of anhydrous ether. The mixture thus-obtained was stirred for fifteen minutes at room temperature and then whilst cooling in an ice bath, 225 milliliters of water were cautiously added, with stirring under nitrogen, thereto. The mixture was further diluted with 2700 milliliters of ether, stirred vigorously for thirty minutes and the ether solution was decanted and saved. The remaining sludge was extracted with three -milliliter portions of ether and the ether solutions so obtained were combined with the ether solution originally obtained. The combined ether solutions were washed with water and dried over sodium sulfate. Evaporation of the solvent gave a solid which was recrystallized from 350 milliliters of acetone to yield 22.087 grams of product melting at 228-235 degrees centigrade. The product so-obtained was again recrystallized from acetone to yield l1,8,17 3-dihydroxy-17a-methyl-5-androsten-3-one 3- ethylene ketal, Compound VIb, having a melting point of 232-236 degrees centigrade.

Analysis.-Calcd. for C H O4: C, 72.89; H, 9.45. Found: C, 72.56; H, 9.39.

C. 5 a,6a-epoxy,1 1 3,1 7,6-dihydroxy-17a-methylandr0stan- 3-0ne 3-ethylene ketal (Compound I Vb) To 3.62 grams of Compound Vlb, 72 milliliters of chloroform and 0.71 gram of anhydrous sodium acetate, cooled in an ice-water bath, there was added seven milliliters of forty percent peracetic acid. The cold reaction mixture thus-obtained was stirred vigorously for two hours, diluted with seventy milliliters of chloroform and seventy milliliters of aqueous saturated sodium bicarbonate solution and then stirred at room temperature for thirty minutes. Upon standing layer separation occurred and the organic (chloroform) layer was removed and saved. The aqueous layer was extracted twice with 200- milliliter portions of chloroform and these extracts were combined with the chloroform extract solution originally obtained. The combined chloroform extract solution was washed with water and dried over sodium sulfate. The chloroform solution was concentrated to seventy milliliters, cooled and the product which precipitated was recovered by filtration. A second crop was obtained by taking the filtrate to dryness and recrystallizing the residue thus-obtained from ethyl acetate-chloroform. The two crops combined gave 2.54 grams of a product decomposing above 280 degrees centigrade. 200 milligrams of the combined product was recrystallized from chloroform-ethyl acetate to yield 5a,6aepoxy-11B,17/3-dihydroxy 17oz methylandrostan-3-one 3-ethylene ketal. Compound IVb, having a melting point of 285295 de grees centigrade (with decomposition) and an [al minus nine degrees (pyridine).

essence Analysis.--Calcd. for (3 mm,; 0, 69.81; H, 9.05. Found: C, 69.56; H, 9.16.

. D. 65 flur0-5ot,1]5,1754rihydroxy-17a-rnethylandrostan-S-one (Compound Vb) To a solution of one gram of Compound IV]; in fifteen milliliters of methylene chloride in a polyethylene bottle there is added three milliliters of 48 percent hydrofiuoric acid. The reaction mixture is stirred vigorously at room temperature for several hours and then carefullypoured, with stirring, into a mixture of six grams of sodium carbonate, 25 milliliters of water and 25 grams of ice. The mixture thus-obtained is stirred for a period of about fifteen minutes and upon standing layer separation occurs. The organic (methylene chloride) solution layer was removed and saved. The aqueous layer was extracted twice with fifty-milliliter portions of methylene chloride and these extracts were combined with the methylene chloride extract solution originally obtained. The combined methylenechloride extract solution is washed with water, dried over sodium sulfate, and the solvent removed to give a crude residuejcontaining 65-fiuoro- 5a,115,175-trihydroxy-17ot-methylandrostan-3-0ne, Compound Vb. This crude residue is then dissolved in 25 milliliters of methylene chloride and chromatographed over fifteen grams of Florisil (synthetic magnesium silicate) and eluted in 25-milliliter fractions with Skellysolve B hexanes plus increasing proportions of acetone from one to fifty percent.

ness leaving a residue.

E. 604 flnosro 115,175 dihydroxy 17a methyl 4 androsten 3-0112 (6ot-flu0ro-115-hydr0xy-17a-methyltestosterone) (Compound 1b) To'the Compound Vb residue'obtained in Example 2, Part D, above, there is added 100 milliliters of chloroform and two milliliters of ethanol. The mixture is cooled to approximately minus ten degrees centigrade and then treated with anhydrous hydrogenvchloride gas for several hours while maintaining the temperature of the solution at approximately minus ten to zero degrees centigrade. The solution thus-obtained is washed with successive portions of water, saturated sodium bicarbon-- ate solution and water, dried over sodium sulfate and then the solvent is removed under reduced pressure leaving a residue. The residue is recrystallized from an acetone- Skellysolve B hexane mixture to give 6a-fi1101O-11B,17I3- dihydroxy-l7u-methyl-4-androsten-3-one, Compound Ib, a crystalline solid which decomposes upon heating at the melting point.

P. 6a flnoro 115,175 dihydroxy 17oz methyl 4 andr sten-.i-one 17-pr0pionate (60t-flLlOIO-11fl-hYdI'OXY- 17ot-methyltestosterone) [Compound Ib(ester)] One, gram of Compound. 112 in ten milliliters of propionicanhydride is heatedat reflux, under nitrogen, until the reaction'is substantially'complete. The reaction mixture is then cooled, poured into 100 milliliters of water and stirred forseveral hours, followed by extraction With ether. The ethereal solution is then washed with sue-'- cessive portions of aqueous ten percent sodium hydroxide solution and water, dried over sodium sulfate, followed by removal of the ether by distillation. The residue remaining following distillation is recrystallized from ace tone-Skellysolve B hexanes to give 6a-fluoro-ll5,l75-dihydroxy 17a methyl-4-androsten-3-one 17-propionate,

Compound Ib(ester), a crystalline solid, which decomposesupon heating at the melting point.

Similarly, by allowing Compound Ib to react with the appropriate hydrocarbon carboxylic' acid anhydride, for example, at temperatures between 100 and 150 degrees centigrade there areproducedother 17-acylates of 60afiuoro 115,175 dihydroxy 17wmethyl- 4 andros- 7 late,

Fractions 5 to 21, contain- 1 ing Compound Vb. are combined and evaporated to dry- 10 ten -S 'One, such as 6a-fluoro-115,175-dihydroxy-17a-methyl'-4-.androsten-3-one- 17-acetate, 6u-flu0ro-115,175-dihydroxy-17a-methyl-4-androsten-3-one 17-butyrate', 6a-fluoro 115,175 dihydroxy 171x methyl 4 androsten 3-one 17-valerate, 6et-fluoro-115,175-dihydroxy17oc-methyl-4-androsten-3-one 17-hexanoate, 6u-fiuoro-l1a,l75-dihydroxy- 17oz methyl-4-androsten-3-one 17-laurate, 6afluoro 115,175 dihydroxy 170a methyl 4 andros-' ten-3-one '17-trimethylacetate, 6ot-fluoro-115,175-dihydroxy-l7a-methyl-4-androsten-3-one 17-isobutyrate, 6al'luoro 115,175 dihydroxy 170a methyl 4 androsten-3-one l7-isovalerate, dot-fluoro-l15,175-dihydroxy- 170a methyl-4-androsten-3-one 17-cyclohexane-carboxy- 6a fluoro-l15,175-dihydroxy-17ot-methyl-4-androsten-3-one l7-benzoate, 6zx-flIlO1'O-11,8,175-dil13'dl0XY-17amethyl 4 androsten-3-one 17-pl1enylacetate, 6a-fiuoro- 115,17,5 dihydroxy 170a methyl 4 androsten 3 one 17 (5 phenylpropionate), 6ot-fluoro-115,175-dihydroxy-17a-methyl-4-androsten-3-one 17-(o-, m-, p-toluate), 6o: fluoro-115,175-dihydroxy-17u-methyl-4-androsten-3-0ne 17-hernisuccinate, which can be converted with sodium-hydroxide to its water-soluble sodium salt, 6oc fluoro 115,175 dihydroxy 17cc methyl 4 andros ten-3-one 17-hemi'adipate, 6ot-fluoro-115,175-dihydroxy- 17oz methyl 4 androsten-'3-one 17-acrylate, 6a-fluoro 115,175-dihydroxy-17ot-methyl-4-androsten-3-one 17-crotonate, 60c fluoro 115,175 dihydroxy-17a-methyl-4-androsen 3 one 17-undecylenate, 6a-fluoro-115,175-dihydroxy 17a methyl-4-androsten-3-one 17-propiolate, 6afiuoro 115,175 dihydroxy 17a methyl 4 androsten-3-one 17-cinnimate, 6a fiuoro 115,175 dihydroxy- EXAMPLE 3 6a,9u difluoro 175- hydroxy 17cc methyl- 4 androstene-3,11 -dione 6 01.,906-di fln'oro-l J -keto-1 7 tat-methyltestouterone) and the 17-propi0nate thereof [Compounds Ic and Ic(ester), respectively] Substituting a stoichiometric equivalent of 9a -fluoro- 175 hydroxy 17ot-methyl-4-androsten-3,1l-dione, compound 'IIc, disclosedin U. S. Patent 2,793,218, for Compound IIa, in Example 1 there is obtained in consecutive order, 90: fiuoro 175-hydroxy-17m-methyl-5-androsten- 3,11-dione 3-ethylene ketal, Compound IIIc (Part A),

. 5a,6a epoxy 9oz fluoro 175 hydroxy 17a methylandrostane 3,11-dione 3-ethylene ketal, Compound IVc (Part B), 65,9oc difluoro 504,175 dihydroxy 17amethy1androstane-3,1l-dione, Compound Vc (Part C),

606,906 difluoro hydroxy 17oz methyl 4 an-- drostene-3,l1-dione, Compound 10 (Part D), and 606,900-

di'fiuoro 175 hydroxy- 17a methyl 4 androstene 3;11-dione 17 -propionate, Compound Ic(ester) (Part E).

EXAMPLE 4 60:,911- difluoro 115,175 dihydroxy 17a methyl 4- androsten 3 one (60:,9a difluoro I15 hydroxy- 17ot-methyltesvoster0ne) and the l7-pr0pi0nate thereof [Compounds Id and Id (ester), respectively] Substituting a stoichiometric equivalent of 9ot-fiuoro- 175 hydroxy 17a-methyl-4'androstents-3,1 l-dione, CompoundI'Ic, for Compound Ila, in Example 2, there is obtained, in consecutive order, 9ot-fluoro-l75-hydroxy- 17bt-methyl-5- androstene-3,1l-di0ne 3-ethylene ketal, Compound IIIc (Part A), 9a-fluoro-115,175-dihydroxy- 17a-methyl-5-androsten-3-one 3-ethylene ketal, Compound VId"(Part B), 5a,6a-epo-xy-9a-fluoro-l15,175-dihydroxy-l7a-methylandrostane-3-one B-ethylene ketal, CompoundlVd (Part C), 65,9ot-difiu0ro-5a,115,175-trihydroxy17bt-methylandrostan-3-one, Compound Vd (Part D), 6a,9wdifluoro 115,175 dihydroxy 17a methyl-4-androsten-3-one, Compound Id (Part E) and '6a,9adifluoro 115,175 dihydroxy 17cc methyl 4 androst en-3-one, Compound 'Id(ester) (Part F).

Alternatively, Compounds Id and Id(ester) are prepared by substituting a stoichiometric equivalent of 9afluoro 115,175 dihydroxy 17 a methyl 4 androsten- 3-one, disclosed in .U. S. Patent 2,793,218, for. Compound -IIa, in Example 1. There is thus-obtained in consecutive order, 9u-fiuoro-115,175-dihydroxy-17a-methy1- 5-,androstene-3,11-dione 3-ethylene ketal (Part A), Compound IVd (Part B), Compound Vd(Part C), Compound Id (Part D), and'Compound Id(ester) (Part F).

EXAMPLE 5 6oz fluoro 175 hydroxy 17cc methyl 19 nor 4- androstene 3,11-diam: (60c fluoro 11 keZo 17amethyl 19 nortestosterone) and the 17-pr0pi0nate thereof [Compounds Ie and Ie(ester), respectively] Substituting a stoichiometric equivalent of 175-hydroxy-17u-methyl-19-nor-4-androstene-3,1 l-dione, Compound IIe, disclosed in U. S. Patent 2,678,933, for Compound Ila, in Example 1, there is obtained, in consecutivev order, 175-hydroxy-17a-methyl-19-nor-5-androstene-3,11-dione 3-ethy1ene ketal, Compound IIIe Part A), 5u,6a-epoxy-175-hydroxy-17a-methyl-19-norandrostane3,11-dione 3-etl1ylene ketal, Compound IVe (Part B), 65-fluoro-5a,175-dihydroxy-l7u-methy1-19-norandrostane-3,l1-dione, Compound Ve(Part C), 6a-fluoro- 175 hydroxy 17a methyl 19 nor 4 androstene- 3,11-dione, Compound Ie (Part D), and 6a-fluoro-175 hydroxy 17cc methyl 19 nor 4 androstene 3,11- -dione 17 propionate, Compound Ie(ester) (Part E).

EXAMPLE 6 6a fluoro 115,175 dihydroxy 17a methyl 19 nor- 4-androsten-3-one (6a-fluoro-115-hydroxy-1 7a-methyl- 19-n0rtest0sterone) and the 17-pr0pi0nate thereof [Compounds I f and 1f( ester), respectively] Substituting a stoichiometric equivalent of 175-hydroxy-17a-methy1-19-nor-4-androstene-3,11-dione, Compound IIe, for Compound Ha, in Example 2, there is obtained, in consecutive order, 175-hydroxy-17a-methyl- 19-nor -5-androstene-3,1l-dione 3-ethylene ketal, Compound IIIe (Part A), 1l5,175-dihydroxy-17u-methyl-19- nor-5-androsten-3-one 3-ethylene ketal, Compound VI (Part B), 5a,60c-p0Xy-11B,17/3-(lihYdI0XY-17oc-II1CthY1- 19-norandrostan-3-one 3-ethylene ketal, Compound IV (Part C), 65-fluoro-5u,115,175-trihydroxy-17a-methyl- 19-norandrostan-3-one, Compound Vf (Part D), 60:- fluoro 115,175 dihydroxy 17oz methyl 19- nor 4- androsten-3-one, Compound If (Part E) and 6a-fiuoro- 115,175 dihydroxy 17oz methyl l9 nor- 4 androsten 3 one 17 4 propionate, Compound lflester) (Part F). n

EXAMPLE 7 6:1,901 difluoro 175 hydroxy 17a methyl 19 nor- 4 androstene 3,11 dione (5a,9oz difluoro 11- keta-I7a-methyl-19-n0rtestoster0ne) and the 17-pr0- pionate thereof [Compounds Ig and Ig (ester), respectively] Substituting a stoichiometric equivalent of 9a-fiuoro- 175 hydroxy 17a methyl-19 nor 4 androstene- 3,11-dione, Compound Hg, for Compound Ha, in Example 1, there is obtained in consecutive order, 90:- fluoro 175 hydroxy 17cc methyl 19 nor 5- androstene-3,11-dione 3-ethylene ketal, Compound I'Hg (Part A), 5a,6a-epoxy-9u-fiu0ro-175-hydroxy-17a-methyl- 19-norandrostane-3,1l-dione 3-ethylene ketal, Compound IVg (Part B), 6a,9u-difiuoro-5 z,175-dihydroXy-17amethyl 19 norandrostane 3,11 dione, Compound Vg (Part C), 6a,9a-difiuoro-175-hydroxy-17u-methy1-19- nor-4-androstene-3,1l-dione, Compound Ig (Part D) and '6u,9a difluoro 175 hydroxy 17cc methyl 19- 12 nor-4 -androstene-3,1l-dione 17 propionate, Compound Ig(ester) (Part E).

Compound Hg used as the starting material is prepared by treating the known'compound l1a,175-dihydroxy-17a-methyl-19-nor-androsten-3-one (1 la-hydroxy- 17-methyl-19-nortestosterone), disclosed in U. S. Patent 2,678,933, according to the procedure disclosed in U. S. Patent 2,793,218.

EXAMPLE 8 6a,9a difln'oro 115,175 dilzydroxy 17cc methyl 19- nor 4 androszen 3 one (6a,9a difluoro hydroxy-I 7u-methyl-19-nortestoszerone) and the 17- propionate thereof [Compounds Ih and Ih(ester) respectively] 1 Substituting a stoichiometricequivalent of 9u-fluoro- 175 hydroxy a methyl 19 nor 4 androstene- 3,11-dione, Compound Hg, for Compound Ha, in Example 2, there is obtained in consecutive order 9a-fiuorohydroxy 17a methyl 19 nor 5 androstene- 3,11dione 3-ethylene ketal, Compound IIIg (Part A), 90: fluoro 115,175 dihydroxy 17cc methyl 19 nor- 5-androsten-3-one 3-ethylene ketal, Compound VIh (Part B), 501,60; epoxy 9a fluoro 115,175 dihydroxy- 17a-methyl-l9-norandrostan-3-one 3-ethylene ketal, Compound IViz (Part C), 6fi-9a-(liflllO-IO-5oc,1I/LI'I'H-Hihydroxy-l7a-methyl-19-norandrostan-3-one, Compound Vh (Part D), 6a9a-difluoro-l15,175-dihydroxy-l7oz-rnethyl- 19-nor-4-androsten-3-one, Com-pound Ih (Part E) and 601,901 difiuoro 115,175-dihydroxy 17a methyl 19- nor-4-androsten-3-one, Compound Ih(ester) (Part F).

Alternatively, Compounds Ih and Ih(ester) are prepared by substituting a stoichiometric equivalent of 9afluoro -1 15,175-dihydroxy-17a-methyl-19-nor-4-androsten- 3 -one,disclosed in U. S. Patent 2,793,218, for Compound 11a, in Example 1. There is thus obtained in consecutive order, 9zx-flUO1'0-1 15,175-dihydroxy-17oc-methyl-19-nor-5- androsten-3-one 3-ethylene ketal (Part A), Compound IVh (Part B), Compound Vh (Part C), Compound Ih (Part D), and Compound Ih (ester) (Part E).

dione Substituting a stoichiometric equivalent amount of 6afluoro -1 15,175-dihydroxy-17a methy1-4-androsten-3-one,

Compound lb, for 115,175 dihydroxy 170a methyl-4- androsten-3-0ne in Example 2 of U. S. Patent 2,793,218 and following the procedures disclosed in Examples 2, 5, 6, 7, and 10 of the patent there is obtained, in consecutive order, 60: fluoro 9(11)- dehydro-175-hydroxy-17arnethyl-4-androsten-3-one, 6a-fluor0-9a-bromo-115,175- dihydroxy-17a-methyl-4-androsten-3-one, 6u-fluoro-9,115- epoxy-175-hydroxy-17a-methyl-4-androsten-3-one, 60,9adifluoro-l 15,175-dihydroxy-17u-methyl-4-androsten-3-one, and 6e,9a-difluoro-175-hydroxy-17m-methyl-4-androstene- 3,11-dione, respectively.

Similarly, substituting a stoichiometn'c equivalent amount of 6u-fluoro-115,175-dihydroxy-17a-methyl-4- androsten-S-one 17-propionate, Compound Ib (ester), for 115,175-dihydroxy-17u-methy1-4-androsten3-one in Example 2 of U. S. Patent 2,793,218 and following the procedures disclosed in Examples 2, 5, 6, 7, and 10 of the patent there is obtained, in consecutive order, 60:- fluoro-9 1 1 -dehydro-175hydroxy-17a -methyl -4-androsten-3-one 17-propionate, 6u-fiu0ro-9a-br0mo-115,175- dihydroxy-17u-methyl-4-androsten-3-one 17-propionate, 6 a-fluoro-9, 1 15-epoxy-175 -h ydroxy- 17 oz methyl-4-androsten-3-one 17-propionate, 6u,9a-difiuoro-115,175-dihydroxy-17a-methyl-4-androsten-3-one 17 propionate, and 6a,9a-difluoro-175hydroxy-17a -methyl-4-androstene-3,1 1- dione 17-propionate, respectively.

. asssmos EXAMPLE 10 Substituting a stoichiometric equivalent'amount of 60afluoro-l 15,175-dihydroXy-170t methyl-19-nor-4-androsten- 3-one, Compound If, for 115,175-dihydroxy-170t-rnethyl 19-nor-4-androsten-3-one in Example 2 of U. S. Patent 2,793,218 and following the procedures disclosed in EX- amples 2, 5, 6, 7, and 10 of the patent there is obtained, in consecutive order, 60t-fiuoro-9(11)-dehydro-175-hydroXy-1700-methyl-l9-nor-4-androsten-3-one, 60t-flUOI'O-9dbromo-1 15,175-dihydroxy-17 t-methyl-19-nor-4-androstennr-4-androsten-3-one, 606,906-dlfl1101'0-1 15,175-dihydroxy- 170c-methyl-19-nor-4-androsten-3-one, and 6a,9a-'difluoro- 175-hydroxy-17a methyl-19-nor-4-androstene -3 ,11- dione, respectively. 0

Similarly, substituting a stoichiomctric equivalent amount of 6a-fluoro-115,175-dihydroxy-17a-methyl-19? nor-4-androsten-3-one 17-propionate, Compound lf(ester), for 115,175-dihydroxy-l70t-methyl-19-nor-4-androsten 3- one in Example 2 of U. S. Patent 2,793,218 and following the procedures disclosed in Examples 2, 5, 6, 7, and 10 of the patent there is obtained, in consecutive order, 60c-fluoro-9( 1 1 )-dehydro-175 hydroxy-170t-methy1-19-nor- 4androsten3-one 17-propionate, 60c-fluoro-9u-bromo-115, 175-dihydroxy-170t-methyl-19-nor-4-androsten-3-one 17- propionate, 60-fiuoro-9,1 -epoxy-175-hydroxyl70t-methyl-19-nor-4-androsten-3-one 17-propionate, 60$,90t-difill0f0- 115,175 dihydroxy -17oc methyl-19-nor-4-androsten-3 -one 17-propionate, and 6a,90edifluoro-175-hydroXy17u-methy1-19-nor-4-androstene-3,1l-dione l7-propionate, respectively.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications wherein R is selected from the group consisting of hydrogen and methyl, R is analkyl radical containing from one to eight carbon atoms, inclusive, R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, Y is selected from the group consisting of hydrogen and fluorine and X. is selected from the group consisting of CHOH and C=O.

2. 60t-fl11OI'O -175 hydroxy- 17 00-alkyl-4-androstene-3 ,1 1- dione in whichthe alkyl radical contains from one to eight carbon atoms, inclusive.

3. 6a-fiuoro-175-hydroxy-17a-methyl-4-androstene-3,1 1- dione.

4. 6a-fiuoro- 17 5 hydroxy-1700 alkyl-4-androstene-3, 1 1- dione 17-acylate in which the alkyl radical contains from one to eight carbon atoms, inclusive, and the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

5. 6a-fiuoro-175-hydroxy-170t-methyl-4-androstene-3 ,1 1- dione l7-propionate.

6. 6 oa-fluoro-l 15,175 dihydroXy-170c alkyl-4-androsten- 1'4 3-one in which the alkyl radical contains from one to eight carbon atoms, inclusive.

7. ,60t-fluoro-1 15,175,dihydroxy-t-methy1-4-androsten- 3-one.

8. 6OL-flUOIO- 1 15,175 dihydroxy-170t alkyl-4-androsten- 3-one 17-acylate in which the alkyl radical contains from one to eight carbon atoms, inclusive, and the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

9. 60 fluoro 115,175 dihydroxy 17oz methyl- 4-androsten-3-one 17-propionate.

10. 606,906" difluoro hydroxy 1700 alkyl 4- androstene-3,11-dione in which the alkyl radical contains from one to eight carbon atoms, inclusive.

11. 601,9a difluoro 175 hydroxy 17a methyl 4- andr0stene-3,1 l-dione.

12. 6a,90z-difluoro 175 hydroxy 17a alkyl- 4- andr0stenej-3,11-dione'17-acylate in which the alkyl radical contains from one to eight carbon atoms, inclusive, and the: acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inelusive.

13. 66:,9wdifluoro 175 hydroxy 17oz methyl- 4-androstene-3,ll-dione 17-propionate.

14. 6:1,900 difluoro 115,175 dihydroxy 170t-a1kyl- 4-androsten-3 one in. which the alkyl radical contains from one to eight carbon atoms, inclusive.

15. 65:,904 difluoro 115,175 dihydroXy-17a-methyl- 4-androsten-3-one.

16. 6on9; difluoro 115,175 dihydroxy 17a-alkyl- 4-androsten-3-one l7 acylate in which the alkyl radical contains'from one to eight carbon atoms, inclusive, and the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

17. 60:,90: difluoro 115,175 dihydroxy 170t-methyl- 4-androsten-3-one 17-propionate.

18. 65 fluoro 11 oxygenated 50 hydroxy 170calkyl compounds of the androstane series having the formula:

OH [MRI X 21. 65 fluoro 500,115,175 trihydroxy 17oz alkylandrostan-3-one in which the alkyl radical contains from one to eight carbon atoms, inclusive.

22. 65 fluoro 504,115,175 trihydroxy 170: methylandrostan-3-one.

23. 65,90: difluoro 504,175 dihydroxy 17a-alkylandrostane-3,11-dione in which the alkyl radical contains from one to eight carbon atoms, inclusive.

24. 65,9a difluoro 50,175 dihydroxy 17a-methyl androstane-3 ,1 l-dione.

25. 65,90; difluoro 500,115,175 trihydroxy 170L- alkylandrostan-3-one in which the alkyl radical contains from one to eight carbon atoms, inclusive.

26. 6 ,9 difluoro 50,41 ,17 trihydroxy 17a wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical containing from one to eight carbon atoms, inclusive, R5 is an alkylene radical containing not more than eight carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least two and not more than three carbon atoms, Y is selected from the group consisting of hydrogen and fluorine and X is selected from the group consisting of CHOH and C=0. I

28. 506,606 epoxy 175 hydroxy 17cc methylandrostane-3,11-dione 3:ethylene ketal.

29. 511,601 epoxy 115,175 dihydroxy 17a methylandrostan-S-one 3-ethylene ketal. 5

30. 501,60; epoxy 90c fluoro 175 hydroxy 17amethylandrostane-3,1l-dione 3-ethylene ketal.

31. 500,60: epoxy 9a fluoro 115,175 dihydroxy- 17a-methyl-androstan-3-one 3-ethylene ketal. p

32. 6a fluoro 17a alkyl compounds of the androstane series having the formula:

wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical containing from one to eight carbon atoms, R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing one to twelve carbon atoms, inclusive, and Z is a halogen having an atomic weight of from 79 to 127.

1 6 33. 6a fluoro 9a bromo 115,175 dihydroxy-17amethyl-4-androsten-3-one.

34. 6a fluoro 9oz bromo 115,175 dihydroxy-17amethyl-4-androsten-3-one 17-propionate.

35. 6oz fluoro 9(11)-dehydro-17u-alkyl compounds of the androstane series having the formula:

wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical containing from one to eight carbon atoms, inclusive, and R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

36. c fluoro 9(11) dehydro hydroxy-17amethyl-4-androsten-3-one.

37. 6o: fluoro 9(11) dehydro 175 hydroxy-17amethyl-4-androsten-3-one 17-propionate.

38. 60c fluoro 9,115 epoxy l7a-alkyl compounds of the androstane series having the formula:

CH2 I---R1 wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical containing from one to eight carbon atoms, inclusive, and R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

39. 6oz fluoro 9,115 epoxy 175 hydroxy 17ozmethyl-4-androsten-3-one.

40. 6oz fiuoro 9,115 epoxy 175 hydroxy 17amethyl-4-androsten-3-one 17-propionate.

No references cited. 

1. 6A-FLUORO-11-OXYGENATED-17A-ALKYL COMPOUNDS OF THE ANDROSTENE SERIES HAVING THE FORMULA: 